Effect of norepinephrine, vasopressin, and dopamine for survivals of the elderly with sepsis and pre-existing heart failure

Our study focused on evaluating the effect of three common vasoactive drugs on the prognosis of elderly patients with sepsis and pre-existing heart failure. The Medical Information Mart for Intensive Care III database, Version 1.4, was used. Our study included critically ill older patients (aged ≥ 65 years) with sepsis and heart failure treated with vasoactive drugs. Patients were divided into norepinephrine group, norepinephrine combined with vasopressin group, and dopamine group. The baseline characteristics, primary outcome, and secondary outcome measures were compared among the three groups. In total, 1357 elderly patients were included (766 in norepinephrine group, 250 in norepinephrine combined with vasopressin group, and 341 in dopamine group). After propensity score matching, statistically significant differences in 28-d and 90-d mortality (P = 0.046, P = 0.031) were observed; meanwhile, there was a significant difference in the incidence of mechanical ventilation, AKI, and malignant arrhythmias. Cox regression analysis revealed that norepinephrine combined with vasopressin decreased 5-year survival statistically(P = 0.001). Multiple linear regression analysis indicated dopamine as an independent risk factor in reducing ICU and hospital length of stay (P = 0.001, P = 0.017). Logistic regression analysis showed dopamine was an independent risk factor for new-onset arrhythmias (P < 0.001), while norepinephrine combined with vasopressin was an independent risk factor for new-onset malignant arrhythmias (P < 0.001). Norepinephrine in combination with vasopressin decreased survival and increased the incidence of malignant arrhythmias in elderly sepsis patients with pre-existing heart failure. Dopamine alone reduces ICU and hospital length of stay but increases the new-onset arrhythmias.


Data source
Data for this study were obtained from the public database Medical Information Mart for Intensive Care (MIMIC III) (https:// mimic.mit.edu) 6 .The version 1.4 MIMIC-III database, maintained by the Massachusetts Institute of Technology Laboratory for Computational Physiology, contains data on patients hospitalized in an ICU at Beth Israel Deaconess Medical Center from 2001 to 2012.One of our authors, ZBH, who was responsible for data extraction, obtained free accessibility to this database after passing the examination of the National Institutes of Health (NIH) online course and gaining the certification (certification No. 36300529).Because the MIMIC-III database is a kind of publicly, available anonymized database, ethical approval was not required.

Study population
For patients readmitted, only the first hospitalization was retained.
Inclusion criteria were as follows: (1) age of 65 years or older; (2) ICU length of stay(LOS) longer than 24 h; (3) diagnosis of sepsis and heart failure; (4) use of norepinephrine, dopamine, or norepinephrine combined with vasopressin boost as a blood pressure maintenance regimen.
Exclusion criteria included the following: (1) age less than 65 years; (2) ICU LOS less than 24 h; (3) no sepsis and no heart failure; (4) no use of norepinephrine, vasopressin, or dopamine; (5) use of a combination regimen of vasoactive drugs other than norepinephrine combined with vasopressin, such as norepinephrine combined with dopamine or vasopressin combined with dopamine.
Sepsis was classified according to the criteria of the 2016 Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) 7 .
All-cause mortality was the primary outcome, including 7-day mortality, 28-day mortality, and 90-day mortality).Several secondary outcome indicators were included: Hospital LOS, ICU LOS, Mechanical Ventilation (MV) incidence, Acute Kidney Injury (AKI) incidence, increased heart rate, new-onset arrhythmia, new-onset malignant arrhythmia, etc. AKI was defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria 8 .Increased heart rate was defined as the gap between the peak HR and the baseline HR extracted from ECG or ECG monitoring.The term "new-onset malignant arrhythmia" is defined as ventricular tachycardia, ventricular fibrillation, and ventricular cardiac arrest.The Vasoactive-Inotropic Score (VIS), a weighted sum of various vasopressors and inotropes, is known to be an independent predictor of adverse outcomes including ventilator days, intensive care unit length of stay, and mortality 9 .
Baseline data were obtained based on the first data within 24 h of ICU admission.If missing, we use the last data before admission to ICU instead.
All scripts used for demographic characterization, clinical scores, and comorbidity were obtained from the GitHub website (https:// github.com/ MIT-LCP/ mimic-code).Data extraction was performed with PostgreSQL tools (v10.0;PostgreSQL Global Development Group) using SQL.

Statistical analysis
As a general rule, continuous variables are reported as medians and interquartile ranges, whereas categorical variables are reported as percentages.Non-parametric data were examined using the Wilcoxon rank-sum test or the Kruskal-Wallis test, whilst parametric data were studied using either analysis of variance (ANOVA).Kolmogorov-Smirnov test was used for Normality Test.
To reduce selection bias and potential confounders, propensity score matching(PSM) method 10 was applied.Variables included in the matching include age, gender, weight, heart rate, CHF, Systolic HF, Diastolic HF, Acute Physiology Score III (APS III), Simplified Acute Physiology Score II (SAPS II), Sequential Organ Failure Assessment (SOFA), Glasgow (GCS) score, blood lactate, bilirubin, oxygenation index, platelets, blood creatinine, blood urea nitrogen, hemoglobin, etc.We set MT to 0.02, selected sampling without replacement, and used Maximize execution performance to perform PSM.Based on log-rank tests, Kaplan-Meier survival curves were analyzed.Cox regression analyses were used to analyze the significance of various variables on survival.
Multiple logistic regression modelling will be used for categorical outcomes and multiple linear regression modelling will be used for continuous variables.Variables with P < 0.1 at univariable analysis were included in a multivariable logistic regression model with a stepwise selection method.Statistical analyses were performed with SPSS version.25 and R version 3.5.3.Bilateral P-value < 0.05 was considered statistically significant.

Results
We found 61,532 records in MIMIC-III v1.4 and finally, 1357 individuals were enrolled.60,175 records were excluded (33,956 for patients < 65 years of Age; 3628 for ICU LOS < 24 h; 12,295 for no sepsis; 6069 for no HF; 2 for the wrong record of LOS; 3023 due to no-use of vasoactive drugs; 365 for non-first ICU admission records; 27 for vasopressin alone and 810 for non-combinations of this study) (Fig. 1).

Baseline demographic information and clinical outcomes
Overall, 1357 patients had an average age of 79.04 years (SD, 7.46 years), 50.7% were male and 72.7% were white.Patients were divided into norepinephrine group (NE group), norepinephrine combined with vasopressin group (NE + VAS group), and dopamine group according to the vasoactive drug used.We found differences existed among the three groups in terms of demographic characteristics, comorbid diseases, and laboratory tests at ICU admission.On clinical scores that reflected the severity of the disease, there were significant differences except for the oxygenation index (PaO 2 /FiO 2 ) (Table 1).To reflect some level of volemic status, the CVP values of each group of patients were shown in Table 1.Among pediatric and adult patients, VIS is known to be an independent predictor of adverse outcomes including ventilator days, intensive care unit length of stay, and mortality 11,12 , so we also analyzed VIS within 6 h, 24 h, 24 to 48 h, and 48 to 72 h after ICU admission.The primary and secondary outcomes were presented in Table 2.

Clinical outcomes after PSM
To balance the baseline factors, we performed PSM.After 1:1 PSM, all of the groups were comparable concerning characteristics (Table 3), however, we found significant differences between 3 groups for outcome variables, especially mortality at 28 days and 90 days (Table 4).

Five-year survival analysis and risk factor
5-year survival analysis of all 1367 patients suggested NE group, dopamine group, and NE + VAS group had significantly different cumulative survival rates (P < 0.001, Fig. 2).After Cox regression models, based on our study population, the combined norepinephrine and vasopressin decreased 5-year survival (HR = 1.346,P = 0.001) (Table 5).

Association with ICU LOS/Hospital LOS
As secondary endpoints, we focused on ICU LOS and Hospital LOS.According to a multivariate linear retrospective model, dopamine alone may shorten ICU LOS and Hospital LOS (Tables 6, 7).
Additionally, as we all know, there were more new-onset arrhythmias observed in patients treated with dopamine than norepinephrine (high-quality evidence) 13 .So we used a logistic regression model to evaluate new-onset arrhythmias incidence and new-onset malignment arrhythmias among the three groups (Tables 8, 9).www.nature.com/scientificreports/Dopamine alone had higher new-onset arrhythmias (OR = 1.665,P < 0.001); norepinephrine combined with vasopressin group had higher malignant arrhythmias (OR = 2.829, P < 0.001).

Discussion
In our study, we found norepinephrine combined with vasopressin worsened outcomes of elderly sepsis patients with heart failure, which suggested this combination was an independent risk factor for 5-year survival.Dopamine alone reduced the Hos Los and ICU Los but had a higher risk of new-onset arrhythmias.
Population ageing is the most important medical and social demographic challenge worldwide 14 .In combination with age-related changes in the human immune system, these immunologic changes may make the elderly particularly susceptible to sepsis 15,16 .Autopsy records for elderly people over 80 in China also confirm that infection-related diseases are the second leading cause of death accounting for 26.6% of all deaths 17 .The   www.nature.com/scientificreports/high global mortality of sepsis 18 is also associated with the failure to keep the hemodynamic status.The choice of vasoactive drugs is more complex and challenging, especially in sepsis patients with heart failure.Dopamine and epinephrine are catecholamines.An early review 19 showed that norepinephrine had an advantage over dopamine in all-cause mortality and the development of arrhythmias in septic shock.SC guidelines also recommend norepinephrine in septic shock 20 .As the first-line treatment in cardiogenic shock, norepinephrine has replaced epinephrine 21 .However, the role of which vasoactive drugs in patients with septic shock with heart failure is still controversial 22 , especially in the elderly.Vasopressin, which is synthesized by the hypothalamic paraventricular and supraoptic nucleus 23 , is recommended as second-line therapy for adults suffering from septic shock with inadequate mean artery pressure levels 24 .However, animal experiments have shown that vasopressin may decrease coronary blood flow 25 .Therefore, we would like to know if norepinephrine combined with vasopressin is appropriate for elderly sepsis patients with heart failure.We found that NE combined with vasopressin may be harmful (28-d, 90-d mortality, and other outcomes) to this study population and has the higher mortality in five-year survival analysis among three groups (P < 0.001).Long-term survival is independently influenced by this combination, which is not consistent with the findings of VASST in 2008 26 .However, the VASST study population did not include patients with NYHA III and IV, and patients were not grouped by age.More interestingly, in 2018, the same VASST Group found that 28-day mortality was significantly higher in NE + vasopressin group than in NE alone(60.8%vs. 46.2%,P = 0.009) in a retrospective study 27 .Although this retrospective analysis also did not group age and cardiac function, it has partially supported our opinion.Second, dopamine alone shortened ICU-LOS and Hos-LOS compared with the other two groups, which sounds good for this population.After regression analysis, it was found that dopamine remained an independent risk factor for new-onset arrhythmias, which is consistent with SOAP II 22 .Meanwhile, NE + vassoprssin was the independent risk factor for new-onset malignant arrhythmias in this study population.We need to consider avoiding this combination in elderly sepsis patients with HF.
This study has the following limitations, first, we conducted a PSM analysis to minimize selection bias in a retrospective study, but the risk of residual unmeasured confounding remains possible.Therefore, the results should be considered in the target population.In addition, the limitations of this study include the lack of each patient's cardiac function and cardiorespiratory endurance before admission.Changes in blood composition may be caused by both pathogens and antibiotics.And volemic status of patients were unknown although we attempted to use CVP and CO reflect.We acknowledge that one of the limitations of our study is that data might be missing from the medical charts.Last, but not least, it was a retrospective single-center study, further multicenter prospective studies are necessary to corroborate our findings.

Conclusions
Taken together, norepinephrine in combination with vasopressin decreased survival and increased the incidence of malignant arrhythmias in elderly sepsis patients with pre-existing heart failure.Dopamine alone reduces ICU and hospital length of stay but increases the new-onset arrhythmias.

Figure 1 .
Figure 1.Workflow of the Study.NE-norepinephrine, LOS-length of stay.

Table 4 .
Clinical outcomes after propensity score matching.NE, norepinephrine; VAS, vasopressin; LOS, length of stay; Hos-LOS, hospital length of stay; AKI, acute kidney injury; VIS, Vasoactive-Inotropic Score.Significant difference between this group and the other 2 groups;# using Fish's exact test.

Table 5 .
Risk factors associated with 5-year mortality in the study population.HR: Hazard ratios; CI: Confidence interval; NE, norepinephrine; VAS, vasopressin; SOFA, sequential organ failure assessment; APS III, Acute Physiology Score III; GCS: Glasgow coma scale; PLT: Platelet; BUN, blood urea nitrogen; HR: heart rate; CHF: congestive heart failure.Univariate analyses with enter method were performed.For multivariate analysis, a forward stepwise selection method was used with covariates showing P-value of less than 0.10 in the univariate analyse.

Table 7 .
Association with hospital length of stay among the three groups.CI: Confidence interval; NE, norepinephrine; VAS, vasopressin; SOFA, sequential organ failure assessment; APS III, Acute Physiology Score III; GCS: Glasgow coma scale; PLT: Platelet; BUN, blood urea nitrogen; HR: heart rate; CHF: congestive heart failure.Variables with P < 0.1 at univariable analysis were included in a multivariable logistic regression model with a stepwise selection method.

Table 8 .
Association with new-onset arrhythmias among the three groups.OR: odds ratio; CI: Confidence interval; NE, norepinephrine; VAS, vasopressin; SOFA, sequential organ failure assessment; APS III, Acute Physiology Score III; GCS: Glasgow coma scale; PLT: Platelet; BUN, blood urea nitrogen; HR: heart rate; CHF: congestive heart failure.Variables with P < 0.1 at univariable analysis were included in a multivariable logistic regression model with a stepwise selection method.

Table 9 .
Association with new-onset malignment arrhythmias among the three groups.OR: odds ratio; CI: Confidence interval; NE, norepinephrine; VAS, vasopressin; SOFA, sequential organ failure assessment; APS III, Acute Physiology Score III; GCS: Glasgow coma scale; PLT: Platelet; BUN, blood urea nitrogen; HR: heart rate; CHF: congestive heart failure.Variables with P < 0.1 at univariable analysis were included in a multivariable logistic regression model with a stepwise selection method.